Porphyromonas gingivalispromotes progression of esophageal squamous cell cancer via TGF beta-dependent Smad/YAP/TAZ signaling

Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance ofPorphyromonas gingivalisis associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC byP.gingivalis. Intracellular invasion ofP.gingivalispotentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-beta (TGF beta)-dependentDrosophilamothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial-mesenchymal transition (EMT) and stemness features. Furthermore,P.gingivalisaugmented secretion and bioactivity of TGF beta through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGF beta axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role ofP.gingivalis.P.gingivalissignature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. TargetingP.gingivalisor its activated effectors may provide novel insights into clinical management of ESCC.